Hand dexterity and pyramidal dysfunction in Friedreich Ataxia, a finger tapping study

Gilles Naeije MD, PhD Antonin Rovai PhD Massimo Pandolfo MD Xavier De Tiège MD, PhD.; Mov Disord Clin Pract. Accepted Author Manuscript. doi:10.1002/mdc3.13126

This study provides evidence for a prominent involvement of pyramidal dysfunction in upper limb dexterity loss as well as a potential outcome measure for clinical studies in FRDA. FRDA patients had slower and more regular FT rate than controls. Eleven FRDA patients showed FT rate slowing. Those patients had longer disease duration and higher SARA scores. Seven patients with FT rate slowing had MEP and all displayed prolonged CMCT, while the four other patients with constant FT rate had normal CMCT.

Progression Characteristics in Friedreich's Ataxia: A 4-Year Observational Study

Reetz, Kathrin and Dogan, Imis and Hilgers, Ralf-Dieter and Giunti, Paola and Mariotti, Caterina and Nanetti, Lorenzo and Durr, Alexandra and Ewenczyk, Claire and Boesch, Sylvia and Nachbauer, Wolfgang and Klopstock, Thomas and Stendel, Claudia and Javier Rodríguez de Rivera Garrido, Francisco and Schöls, Ludger and Hayer, Stefanie and Klockgether, Thomas and Giordano, Ilaria and Didszun, Claire and Rai, Myriam and Pandolfo, Massimo and Schulz, Jörg B. and Group, EFACTS Study. "Preprints with The Lancetare are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed". doi:10.2139/ssrn.3723615

Background: The European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich’s ataxia (FRDA) in a prospective multinational registry study. We aimed to assess progression and metric characteristics of clinical rating scales based on longitudinal 4-year data.

Antiferroptotic Activity of Phenothiazine Analogues: A Novel Therapeutic Strategy for Oxidative Stress Related Disease

Jun Liu, Indrajit Bandyopadhyay, Lei Zheng, Omar M. Khdour, and Sidney M. Hecht; ACS Med. Chem. Lett. 2020, 11, 11, 2165–2173,  September 15, 2020, doi:10.1021/acsmedchemlett.0c00293.

Recently, we showed that lipophilic methylene blue (MB) and methylene violet (MV) analogues both promoted increased frataxin levels and mitochondrial biogenesis, in addition to their antioxidant activity in cultured FRDA cells. Presently, we report the synthesis of series of lipophilic phenothiazine analogues that potently inhibit ferroptosis. The most promising compounds (1b–5b) exhibited an improved protection compared to the parent phenothiazine against erastin- and RSL3-induced ferroptotic cell death. These analogues have equivalent or better potency than ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), that are among the most potent inhibitors of this regulated cell death described so far. They represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models such as FRDA.

Analysis of Postural Control in Sitting by Pressure Mapping in Patients with Multiple Sclerosis, Spinal Cord Injury and Friedreich’s Ataxia: A Case Series Study

Reguera-García, M.M.; Leirós-Rodríguez, R.; Álvarez-Barrio, L.; Alonso-Cortés Fradejas, B.; Sensors 2020, 20, 6488.

The tests applied were: pressure mapping, seated Lateral Reach Test, seated Functional Reach Test, Berg Balance Scale, Posture and Postural Ability Scale, Function in Sitting Test, and Trunk Control Test. The participants with Friedreich’s ataxia showed a tendency to present a higher mean pressure on the seat of subject’s wheelchair compared to other groups. In parallel, users with spinal cord injury showed a tendency to present the highest values of maximum pressure and area of contact. People with different neurological pathologies and similar results in functional tests have very different results in the pressure mapping. Although it is not possible to establish a strong statistical correlation, the relationships between the pressure mapping variables and the functional tests seem to be numerous, especially in the multiple sclerosis group.

Left ventricular unloading with transaortic Impella 2.5 implantation in a pediatric patient supported by ECLS.

Sandoval Boburg, R., Mustafi, M., Magunia, H., Kling, S., Schlensak, C. and Popov, A.‐F., Artificial Organs. Accepted Author Manuscript. (2020) doi:10.1111/aor.13862 

We report the case of a 12-year old female patient with Friedreich´s Ataxia and diabetes mellitus. Due to a progressive multi-organ failure a veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was implanted through the axillary vessels. However, due to a lack of ejection and severe dilatation of the left ventricle, an Impella 2.5 was implanted. Due to the small diameter of the femoral arteries, we performed a trans-aortic implantation through a median sternotomy via a dacron tube graft. We report on the procedure and peri-operative outcome.

Minoryx’s preclinical data for leriglitazone in Friedreich’s Ataxia published in Neurobiology of Disease Journal

Mataró, Barcelona, Spain and Gosselies, Belgium, November 16, 2020 – Minoryx Therapeutics, a Phase 3 clinical stage biotech company focused on the development of differentiating treatment options in orphan central nervous system (CNS) disorders with high unmet need, today announces the publication in ‘Neurobiology of disease’ of preclinical data on its lead compound, leriglitazone, showing potential therapeutic action and protection against neurodegeneration, in particular against Friedreich’s Ataxia (FRDA).

The preclinical data, published on November 7, 2020, supports the on-going clinical development in treating FRDA. The results show that the company’s lead compound, leriglitazone, improves impairments that are derived from frataxin loss – the genetic deficiency that causes FRDA.

Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease

La Rosa, P.; Petrillo, S.; Fiorenza, M.T.; Bertini, E.S.; Piemonte, F.; Biomolecules 2020, 10, 1551. doi:10.3390/biom10111551 

This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress.

Cardiomyopathy as the first manifestation of Friedreich's ataxia

Rafael Tuzino Leite Neves Maffei; Giulio de los Santos Fortuna; Luca Campolino Rosso; Pedro Dragone Pires; Ivan Rondelli Autops Case Rep, vol.10, n3, e2020204, 2020; doi:10.4322/acr.2020.204 

 We present the case of a female patient diagnosed in childhood with Friedreich Ataxia (FA). At the age of 6, she developed left congestive heart failure with cardiomyopathy, as evident on echocardiogram. Neurologic signs only appeared at age 7, including marked loss of muscle mass, gait instability, muscle clonus, and Babinski's signal. At age 27, she had a stroke and was hospitalized; a few days later, she had a cardiorespiratory arrest with asystole, leading to death. The autopsy disclosed severe cardiomyopathy and significant myocardial replacement with fibrosis; therefore, the cause of death was assumed to be heart failure. Compared to the literature, our case has some unique features, such as cardiac disease as the presenting manifestation instead of gait instability, which is the major initial sign in most FA cases. Since our patient was submitted to an autopsy, it was an opportunity to retrieve important data to confirm the diagnosis and to evaluate the pathophysiology of this entity, such as myocardium fibrosis and cerebellar degeneration. In summary, our case demonstrates that cardiac disease can be the first manifestation of FA, with eventual diagnostic and prognostic implications. In addition, the autopsy provided findings of severe cardiomyopathy associated with FA.

Epigenetic Regulation of the Clinical Signs of Friedreich’s Disease

E. P. Nuzhny, N. Yu. Abramycheva, N. S. Nikolaeva, M. V. Ershova, S. A. Klyushnikov, S. N. Illarioshkin & E. Yu. Fedotova; Neurosci Behav Physi (2020). doi:10.1007/s11055-020-00998-9 

Studies of genetic-epigenetic interactions identified correlations between the extent of methylation of a series of CpG sites in the UP-GAA and DOWN-GAA and the number of GAA repeats in both expanded alleles of the FXN gene in patients with FD. We also found a link between methylation and the presence of the extraneural signs of FD: cardiomyopathy was more likely to be present when the CpG site of the promoter region was hypermethylated, while impairments to carbohydrate metabolism were more common in hypomethylation of CpG sites in the DOWN-GAA area. Conclusions. The data obtained here provide evidence that epigenetic modifications of the FXN gene make a significant contribution to forming the clinical picture of FD.

The Nrf2 induction prevents ferroptosis in Friedreich’s Ataxia

Piergiorgio La Rosa, Sara Petrillo, Riccardo Turchi, Francesco Berardinelli, Tommaso Schirinzi, Gessica Vasco, Daniele Lettieri-Barbato, Maria Teresa Fiorenza, Enrico S. Bertini, Katia Aquilano, Fiorella Piemonte, Redox Biology, 2020, 101791, doi:10.1016/j.redox.2020.101791.

Ferroptosis is an iron-dependent cell death caused by impaired glutathione metabolism, lipid peroxidation and mitochondrial failure. Emerging evidences report a role for ferroptosis in Friedreich’s Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2 signalling is implicated in many molecular aspects of ferroptosis, by upstream regulating glutathione homeostasis, mitochondrial function and lipid metabolism. As Nrf2 is down-regulated in FRDA, targeting Nrf2-mediated ferroptosis in FRDA may be an attractive option to counteract neurodegeneration in such disease, thus paving the way to new therapeutic opportunities. In this study, we evaluated ferroptosis hallmarks in frataxin-silenced mouse myoblasts, in hearts of a frataxin Knockin/Knockout (KIKO) mouse model, in skin fibroblasts and blood of patients, particularly focusing on ferroptosis-driven gene expression, mitochondrial impairment and lipid peroxidation. The efficacy of Nrf2 inducers to neutralize ferroptosis has been also evaluated.